PROJECT SUMMARY Severe acute respiratory infections (SARI) are a leading cause of death and hospitalization in children. In the U.S., almost half of the children who will progress to acute respiratory failure from SARI have no predisposing conditions to explain such severe illness. Although the majority of these children will survive if they receive targeted antimicrobials and mechanical ventilator support, many will develop severe multiple organ dysfunction syndrome (MODS). Many children with MODS will die if both their cardiovascular and respiratory systems fail. Major opportunity exists to save lives and more rapidly reverse organ failure if clinicians understood how to optimally modulate the immune response of a child with SARI. Unfortunately, there is a paucity of data differentiating a productive from a pathologic immune response in these children. Cases of near-fatal and fatal SARI have been characterized by excessive inflammation and by profound secondary immune suppression; in some children both processes occur at the same time. The objective of this study is to identify genes and gene biosignatures associated with severe MODS and MODS-related subtypes and outcomes in critically ill children with SARI. We already recruited over 450 children with SARI admitted to the pediatric intensive care unit (ICU) with suspected influenza infection (PICFLU) to evaluate genes that influence their immune response. Using the rich clinical repository and biobank from the PICFLU study, we will generate mRNA gene expression data from over 600 immune-related genes using existing blood and respiratory samples. In Aim 1 we will evaluate whole identify genes and gene pathways that (a) distinguish children with very severe lung and cardiovascular organ failure from those with less severe organ dysfunction and (b) predict by ICU day 3 which patients will survive and resolve cardiorespiratory organ failure within 2 weeks versus have more prolonged failure and/or die. In Aim 2 we will identify the mRNA biomarker signature associated with MODS-related innate immune suppression (immunoparalysis) in children with SARI using whole blood samples. We hypothesize that by using an unbiased data driven approach to gene and gene pathway discovery in SARI, we will identify new therapeutic targets that have previously been overlooked. We expect to identify multiple new gene pathways and genes associated with MODS and MODS-phenotypes. This work will pave the way for future precision medicine where immune-related treatments are targeted at those children presenting with or developing the most severe subtypes of MODS. Novel treatments resulting from this work could have a global impact on improving SARI survival and in optimizing recovery from SARI-related organ failure.